The vagina is a fibromuscular tubular tract leading from the uterus to the exterior of the body in females. A healthy vagina is colonized by a mutually symbiotic flora of microorganisms, in particular lactobacilli, that protect its host from vaginal infections. The acidity of a healthy vagina of a woman of child-bearing age (pH about 3.8-4.5) is due to the degradation of secreted glycogen/glucose to lactic acid and acetate by lactobacilli (Boskey et al., 2001). Said acidity being unfavourable for the growth of many pathogenic microorganisms, including bacteria, protozoa and viruses. However, any imbalance in said vaginal ecosystem may result in overgrowth of pathogenic microorganisms, resulting in vaginal infections.
Multiple kinds of vaginal infections (vaginitis) exist, depending on the pathogenic microorganism involved such as bacterial vaginosis, vaginal candidiasis and trichomoniasis and combinations thereof.
Bacterial vaginosis is the most common cause of vaginal infections, and is associated with complications during pregnancy as well as an increased risk for sexually transmitted diseases. It is caused by an imbalance of naturally occurring bacterial flora, wherein the lactobacilli are overgrown by a mixed flora of anaerobic bacteria. Amongst other diagnostic criteria, a pH greater than 4.5 is considered to be suggestive of bacterial vaginosis. Current treatment options rely on oral or vaginal administration of classical antibiotics such as metronidazole and clindamiycine, however there is a rate of recurrence of over 50% within 3 months after the first exposure (Verstraeten & Verhelst, 2009). Alternative treatment options include acidification of the vagina with naturally occurring acids such as lactic acid or acetate. For example, Andersch et al. treated 42 women having recurrent bacterial vaginosis, with an intravaginal lactic acid gel. After 6 months of treatment 88% of women from the treated group had a normal vaginal microflora in contrast to 16% of women in the placebo group (Andersch et al., 1990).
Vaginal candidiasis is a fungal infection of any of the Candida species (yeasts), of which Candida albicans is the most common. Most candidial infections are treatable and result in only minimal complications such as redness or itching, however complications may also be severe or even fatal if left untreated in certain populations such as immuno-compromised patients. External use of detergents or internal disturbances (hormonal or physiological) can disturb the normal vaginal flora and result in an overgrowth of Candida cells causing infection. Also pregnancy and the use of oral contraceptives have been reported as risk factors. In clinical settings, candidiasis is commonly treated with antimycotics such as clotrimazole, nystatin, fluconazole and ketoconazole. However, C. albicans can develop resistance to said antimycotic drugs, so alternative treatment options are desired.
Trichomoniasis is a sexually transmitted disease of the urogenital tract and is caused by the single-celled protozoan parasite Trichomonas vaginalis. Symptoms include inflammation of the cervix, urethra and vagina, which produce an itching and burning sensation. Current treatment options include the use of the antibiotic/anti-protozoal (metronidazole) or anti-parasitic (tinidazole) drugs. However, as with most anti-microbial drugs, resistance may occur, thereby underscoring the need for alternative treatment options.
Therefore, alternative treatment options, not making use of antibiotics or other kinds of drugs, for vaginal infections and sexually transmitted diseases have been suggested and may reside in the application of acidic compounds (for lowering the pH) or naturally occurring vaginal bacterial strains. However, most currently available products make use of gel-like formulations requiring multiple daily applications, requiring a lot of effort and commitment of the patient. It would therefore be highly advantageous to provide a controlled-release product, for delivery of active ingredients, in particular organic acids, thereby no longer requiring multiple applications per day, but for example only once every few days or even once every few weeks.
It was therefore an object of the present invention to provide an intravaginal delivery system for the controlled release of organic acids, in particular lactic acid.
Although intravaginal delivery systems for the controlled release of active ingredients have been described before, most of them do not comprise organic acids as an active ingredient.
For example WO2006065873 provides an intravaginal flat porous mesh encircled with a fiber-reinforced composite ring, said ring comprising an elastomeric copolymeric matrix, such as for example glycolide copolymers, carbonate copolymers and silicone polymers. This porous mesh is provided for the controlled delivery of at least one bioactive agent. Furthermore, any organic acid present in the device is merely used as an excipient in addition to the bioactive agent(s), not as an active ingredient itself (e.g. example 10 of WO2006065873). US20070196433 provides a two-segmental drug delivery device comprising a drug-permeable polymeric substance, such as for example an ethylene-vinyl acetate copolymer. However, again, amongst the active ingredients no organic acids are mentioned, but they rather include pharmaceutical drugs, such as antibiotics. WO2009066006 provides an intravaginal delivery system for the controlled release of pharmaceuticals, in particular drospirenone and estradiol, said delivery system comprising one or more polymers selected from a long list of possibilities. However, the only exemplified delivery system comprises the commonly used PEO-b-PDMS (polyethyleneoxide-b-poly (dimethylsiloxane)) copolymer. Again, this delivery system may further comprise organic acids, but none of the exemplified systems comprises one or more organic acids as the main active ingredient.
WO2010133761 provides an intravaginal polymeric delivery system comprising at least one active ingredient, including acidic compounds or beneficial microorganism. However, again suitable polymers may be selected from a long list of possible polymers including combinations thereof, with the only exemplified polymer combination being the commonly used PEO-b-PDMS (polyethyleneoxide-b-poly (dimethylsiloxane)) copolymer.
Evidently, when trying to incorporate pharmaceutically relevant levels of organic acids in a certain polymeric environments, it is not to be excluded that one may encounter undesired reactivity. Furthermore, in order to achieve a controlled release of the organic acid from the delivery system, the polymeric environment should not only be compatible with the presence of pharmaceutically relevant levels of organic acids, but also allow a controlled release from the delivery device. Therefore, one cannot simply take any available intravaginal delivery system and replace the used active ingredient by a pharmaceutically relevant concentration of one or more organic acids.
To the best of our knowledge, only 1 publication describes an intravaginal delivery system comprising organic acid(s) as the main active ingredient (WO2010/133761). In this publication, only the commonly used PEO-b-PDMS (polyethyleneoxide-b-poly (dimethylsiloxane)) copolymer was used and folic acid was incorporated therein (example 1). However, no data regarding the release profile of said folic acid are provided, questioning whether this device would be useful for the controlled release of organic acids. Furthermore, as evident from the examples hereinafter, cationic polymers, have been found not to be useful for preparing a controlled release delivery system.
In contrast, we have found that a delivery system comprising one or more EVA (ethylene vinyl acetate) copolymers and one or more carboxylic polymers is very suitable for the controlled release of organic acids.